State-Based Biological Communication

Allostery (1) is the process through which proteins self-regulate in response to various stimuli. Allosteric interactions occur between nonadjacent spatially distant residues (1), and they are exhibited through the correlated motions (2) and momenta of participating residues. The location of allosteric sites in proteins can be determined experimentally but computational methods to predict the location of allosteric sites are being developed as well (2-4, 10). Experimental and computational methodologies for locating allosteric sites can be used to design specific targeted drug delivery (5-6, 19), but these methods have not yet fully explained a mechanism for allosteric communications. An allosteric pathway is a chain of residues that “communicate” by frequently colliding into one another. The frequency of collisions causes members of the chain to transfer kinetic energy amongst each other preferentially (3-4). Allosteric pathways begin and end at protein binding sites. An allosteric event occurs when an external molecule interacts with a binding site. An allosteric process is triggered by an allosteric event (7-9), and it is a consequence of a protein’s free energy landscape changing in response to the stimuli (12). The protein begins to assume a new conformation due to the changes in its free energy landscape, and as its structure changes its functionality also changes as the system approaches a new equilibria. At equilibrium, a protein’s conformational ensemble remains stable, and the residues participating in an allosteric pathway remain fairly constant (3). The frequent collisions along allosteric pathways lead to quantifiable mathematical patterns in the physical states (position, momentum, internal energy) of allosteric pathway residues over time. Non-allosteric pathway residues also collide with other residues but will not display a discernable pattern in physical state with other residues over time. Current computational methods for quantifying patterns in physical state to identify allosteric pathways utilize Percolation Theory (3), Isotropic Heat Diffusion (4), Direct Cross Correlation (2), and Information Theory (11, 13). This work strives to enhance the Information Theoretic approach for locating allosteric sites and use this new perspective to develop a model to describe protein communication. The Information Theoretic approach has been chosen due to its ability to capture dynamic, nonlinear relationships, at relevant biological temperatures. Mutual Information (MI) quantifies the information that two variables share (5), and it will be used in this work to examine signaling relationships between a protein’s residues at equilibrium. There is evidence to suggest that allosteric signals travel along energy pathways through transfers of kinetic energy between colliding residues (3-4). This work hypothesizes that a pattern of collisions forms during equilibria via repetitive kinetic energy transfers between residues along an allosteric pathway. If the energy transferred during this process functions as a repetitive biological ‘signal’ then there will be quantifiable patterns in physical state data that Mutual Information can be used to characterize analytically

Quantified Uncertainty of Flexible Protein-Protein Docking Algorithms

The strength or weakness of an algorithm is ultimately governed by the confidence of its result. When the domain of the problem is large (e.g. traversal of a high-dimensional space), an exact solution often cannot be obtained, so approximations must be made. These approximations often lead to a reported quantity of interest (QOI) which varies between runs, decreasing the confidence of any single run. When the algorithm further computes this QOI based on uncertain or noisy data, the variability (or lack of confidence) of the QOI increases. Unbounded, these two sources of uncertainty (algorithmic approximations and uncertainty in input data) can result in a reported statistic that has low correlation with ground truth. In molecular biology applications, this is especially applicable, as the search space is generally large and observations are often noisy. This research applies uncertainty quantification techniques to the difficult protein-protein docking problem, where uncertainties arise from the explicit conversion from continuous to discrete space for protein representation (introducing some uncertainty in the input data), as well as discrete sampling of the conformations. It describes the variability that exists in existing software, and then provides a method for computing probabilistic certificates in the form of Chernoff-like bounds. Finally, this paper leverages these probabilistic certificates to accurately bound the uncertainty in docking from two docking algorithms, providing a QOI that is both robust and statistically meaningful

Are the Goals of Sustainability Interconnected? A Sociological Analysis of the Three E’s of Sustainable Development Using Cross-Lagged Models with Reciprocal Effects

Conceptual discussions of sustainability emphasize the interdependent relationship between relevant social and environmental factors. Yet, traditional quantitative analyses of the topic have tended to estimate the exogenous or direct/indirect effects a predictor variable has on a particular measure of sustainability. We examine the endogenous, interdependent relationship between the three E’s of sustainability (economy, equity, and ecology), incorporating country-level data for 1990 through 2015 into cross-lagged structural equation models with reciprocal and fixed effects. Results from these longitudinal models suggest that over time, at the country level, increasing economic inequality reduces renewable energy consumption, with no evidence of reciprocal feedback. Keeping in mind the limitations of the analysis, we tentatively argue that the modern form of development has constrained the potential for the sustainability goals to feed back into each other

Interstitial lung diseases in children

Interstitial lung disease (ILD) in infants and children comprises a large spectrum of rare respiratory disorders that are mostly chronic and associated with high morbidity and mortality. These disorders are characterized by inflammatory and fibrotic changes that affect alveolar walls. Typical features of ILD include dyspnea, diffuse infiltrates on chest radiographs, and abnormal pulmonary function tests with restrictive ventilatory defect and/or impaired gas exchange. Many pathological situations can impair gas exchange and, therefore, may contribute to progressive lung damage and ILD. Consequently, diagnosis approach needs to be structured with a clinical evaluation requiring a careful history paying attention to exposures and systemic diseases. Several classifications for ILD have been proposed but none is entirely satisfactory especially in children. The present article reviews current concepts of pathophysiological mechanisms, etiology and diagnostic approaches, as well as therapeutic strategies. The following diagnostic grouping is used to discuss the various causes of pediatric ILD: 1) exposure-related ILD; 2) systemic disease-associated ILD; 3) alveolar structure disorder-associated ILD; and 4) ILD specific to infancy. Therapeutic options include mainly anti-inflammatory, immunosuppressive, and/or anti-fibrotic drugs. The outcome is highly variable with a mortality rate around 15%. An overall favorable response to corticosteroid therapy is observed in around 50% of cases, often associated with sequelae such as limited exercise tolerance or the need for long-term oxygen therapy

Prompt Reversal of Airway Obstruction Secondary to Angiotensin Converting Enzyme Inhibitor (ACEI) Induced Angioedema by Ecallantide: A Case Report

Case: A 54 year old African-American male with a history of hypertension treated with lisinopril daily, remote cocaine abuse associated myocardial infarction, seizures and prostate cancer, presented with a 2 day history of facial and throat swelling along with dysphagia. He was treated in the emergency department with intravenous methylprednisolone, epinephrine and diphenhydramine. He was admitted, but angioedema progressed overnight, confirmed by laryngoscopy. ICU transfer and intubation was undertaken the next morning for airway protection. Tryptase level was 2 ng/ml. C3 and C4 and routine chemistries were normal. Ecallantide 30mg was administered subcutaneously at 1014 hours. Presented at: American Academy of Allergy Asthma and Immunology annual conference in Orlando Florida